Atomoxetine

7 DRUG INTERACTIONS Monoamine Oxidase Inhibitors. ( 4.2 , 7.1 ) CYP2D6 Inhibitors - Concomitant use may increase atomoxetinesteady-state plasma concentrations in EMs. (7.2) Antihypertensive Drugs and Pressor Agents - Possible effects on blood pressure. (7.3) Albuterol (or other beta 2 agonists) - Action of albuterol on cardiovascular system can be potentiated. (7.4) 7.1 Monoamine Oxidase Inhibitors With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Contraindications (4.2) ] . 7.2 Effect of CYP2D6 Inhibitors on Atomoxetine In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and C ss, max is about 3- to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. 7.3 Antihypertensive Drugs and Pressor Agents Because of possible effects on blood pressure, atomoxetine hydrochloride should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure. 7.4 Albuterol Atomoxetine hydrochloride should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta 2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200 to 800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status. 7.5 Effect of Atomoxetine on P450 Enzymes Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. CYP3A Substrate (e.g., Midazolam ) - Coadministration of atomoxetine hydrochloride (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A. CYP2D6 Substrate (e.g., Desipramine) - Coadministration of atomoxetine hydrochloride (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6. 7.6 Alcohol Consumption of ethanol with atomoxetine hydrochloride did not change the intoxicating effects of ethanol. 7.7 Methylphenidate Coadministration of methylphenidate with atomoxetine hydrochloride did not increase cardiovascular effects beyond those seen with methylphenidate alone. 7.8 Drugs Highly Bound to Plasma Protein In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin. 7.9 Drugs that Affect Gastric pH Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on atomoxetine hydrochloride bioavailability.

STRATTERA is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). The label notes it should be used as part of "a total treatment program for ADHD that may include other measures (psychological, educational, social)."

2 DOSAGE AND ADMINISTRATION Initial, Target and Maximum Daily Dose (2.1) (Acute and Maintenance/Extended Treatment) Body Weight Initial Daily Dose Target Total Daily Dose Maximum Daily Dose Total Children and adolescents up to 70 kg 0.5 mg/kg 1.2 mg/kg 1.4 mg/kg Children and adolescents over 70 kg and adults 40 mg 80 mg 100 mg Dosing adjustment – Hepatic Impairment, Strong CYP2D6 Inhibitor, and in patients known to be CYP2D6 poor metabolizers (PMs). ( 2.5 , 12.3 ) 2.1 Acute Treatment Dosing of children and adolescents up to 70 kg body weight - Atomoxetine capsules should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day [see Clinical Studies (14) ]. The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. Dosing of children and adolescents over 70 kg body weight and adults - Atomoxetine capsules should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses [see Clinical Studies (14) ]. The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg. 2.2 Maintenance/Extended Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6 to 15 years) with ADHD on atomoxetine hydrochloride after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial. Patients assigned to atomoxetine hydrochloride in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use atomoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Clinical Studies (14.1) ]. 2.3 General Dosing Information Atomoxetine capsules may be taken with or without food. Atomoxetine capsules can be discontinued without being tapered. Atomoxetine capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information ( 17 )] . The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated. 2.4 Screen for Bipolar Disorder Prior to Starting Atomoxetine Prior to initiating treatment with atomoxetine, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.6 )]. 2.5 Dosing in Specific Populations Dosing adjustment for hepatically impaired patients - For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal [see Use In Specific Populations ( 8.6 ) ] . Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs - In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, atomoxetine hydrochloride should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, atomoxetine capsules should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

In children/adolescents, most common reactions (≥5% and twice placebo) include "nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence." In adults, most common reactions include "constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation." Serious postmarketing reports include seizures, QT prolongation, syncope, rhabdomyolysis, priapism, and severe liver injury including cases requiring transplant.